The present invention relates to crystalline solvates of 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril, also known as aripiprazole and to the making and using of the same.
Aripiprazole is a compound of the formula (1).
It is a commercially marketed, pharmaceutically active substance useful for treatment of schizophrenia. It is disclosed in EP 367141/U.S. Pat. No. 5,006,528. The commercially marketed product contains the compound (1) as the free base; i.e., not as an aripiprazole salt.
Solid state aripiprazole was prepared in U.S. Pat. No. 5,006,528 by a two-fold recrystallization of crude aripiprazole from ethanol resulting in colorless flake crystals having a melting point of 139-139.5° C. In an article of Aoki (Study on Crystal Transformation of Aripiprazole, The Fourth Japan-Korea Symposium on Separation Technology, p. 937 ff (1996)), this solid state form was designated as Type I aripiprazole and identified as an anhydrate. Aoki also teaches that the Type I aripiprazole may be converted into a Type II aripiprazole by heating at 130-140° C. for 15 hours. This product is an anhydrate as well with a melting point of 150° C. When both Type I and Type II aripiprazole were recrystallized from an alcoholic solvent containing water up to 20%, the product was an aripiprazole hydrate labeled as Type III by Aoki. Type III aripiprazole can be converted into the Type I by heating at 80° C.
WO 03/26659 (EP 1330249) teaches that Type I aripiprazole, the alleged original solid form of aripiprazole, is significantly hygroscopic. In an effort to find a form of aripiprazole having reduced hygroscopicity and better processing qualities, seven crystalline forms (A-G) were described.
Hydrate Form A is taught as a useful intermediate for making anhydrate forms. Hydrate Form A can be prepared by milling Aoki's hydrated Type III.
Anhydrous Form B, which seems to be the preferred crystalline form, is not hygroscopic; i.e., less than 0.4% water uptake in 24 hours, and is a stable crystalline form. It can be prepared by heating the Hydrated Form A, preferably at 90-125° C. for 3-50 hours or by heating the Type I/Type II aripiprazole at 90-125° C.
The other anhydrate forms disclosed therein are briefly summarized below.
Form C: Prepared by heating an aripiprazole anhydrate to 140-150° C. Endothermic peak around 150.2° C.
Form D: Prepared by recrystallization of aripiprazole anhydrate from toluene. Endothermic peaks at 136.8 and 141.6° C.
Form E: Prepared by double heating, dissolving, and crystallizing aripiprazole in acetonitrile with crystallization at about 70° C. Endothermic peak at 146.5° C.
Form F: Prepared by heating a suspension of aripiprazole anhydrate in acetone. Endothermic peaks at 137.5 and 149.8° C.
Form G: Prepared by putting glassy state of aripiprazole anhydrate in a sealed vessel and keeping it at room temperature for at least 2 weeks. Exothermic peak at 122.7° C., endothermic peak at 141.0° C.
In particular, it would be desirable to find other crystalline forms of aripiprazole, particularly preparable in a reliable process on an industrial scale. Furthermore, it would be desirable to find alternate processes for making useful crystalline forms of aripiprazole, especially Form B aripiprazole.